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Abstract

We present here an intriguing case of sporadic renal haemangioblastoma occurring in
a 61-year-old male. The tumor consisted of nests of polygonal cells and abundant capillary
networks. The neoplastic cells generally showed abundant eosinophilic cytoplasm and
prominent eccentric nuclei, resembling the rhabdoid cells. Pronounced intranuclear
cytoplasmic pseudoinclusions were another significant feature seen. NSE, a-inhibin
and S100 were positive in tumor cells and particularly, focal CD10 expressions were
observed. This is possibly the first reported case of a haemangioblastoma showing
a rhabdoid phenotype and CD10 immunopositivity. Malignant rhabdoid tumor and renal
cell carcinoma with rhabdoid features were probably the most challenging mimics need
to be differentiated. The result of focal CD10 staining in our case may further lead
to confusion with renal cell carcinoma. To avoid misdiagnosis, more considerations
should be attached to the rare neoplasm.

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Keywords:

Background

Haemangioblastoma is a slowly growing, highly vascular benign tumor, corresponding
to WHO grade I. It typically arises within the central nervous system (CNS), but may
occasionally originate in unusual sites such as peripheral nerve, bone, soft tissue,
skin, liver, lung and pancreas [1-3], and maybe associated with von Hippel-Lindau (VHL) disease.

The kidney is another rare site for the development of sporadic haemangioblastoma
growth, and only four cases have been reported in the English-language literature
so far [4-6]. The accurate diagnosis is often challenging when the tumor develops in this region.
We described herein the fifth case of this rare tumor, which notably demonstrated
a rhabdoid phenotype as well as unexpected CD10 staining. In addition, the shared
characteristics of renal haemangioblastomas (RHB) and their differential considerations
were also discussed in detail.

Case presentation

A 61-year-old man was admitted to our hospital for a solid mass found in the right
kidney during a routine checkup. Computed tomography showed that the mass was located
in the superior pole. No remarkable symptoms such as flank pain or urinary irritation
were reported by the patient. He also had no familial history or clinical evidences
of VHL disease. Radical nephrectomy was carried out, showing a 5.3 × 5.0 × 5.0 cm
mass. It was grey to yellowish in color and well-demarcated from the surrounding renal
parenchyma. The patient had an uneventful postoperative recovery and was well at 12
months follow-up.

Histopathological and Immunohistochemical findings

Microscopically, the specimen consisted of nests of polygonal tumor cells and a prominent
capillary network. Focal areas of necrosis were present. The stroma showed extensive
fibrosis and hyalinization, which amounted to approximately one third of the lesion
(Figure 1A, B).

Figure 1.Histopathological findings of the renal hemangioblastoma. (A) Stromal hyalinization was prominent among the neoplasm and foci of necrosis were
observed inside the tumor (left field) (H&E staining, with original magnification
×40). (B) The tumor cells were arranged in nests and traversed by a vascular network (H&E
staining, with original magnification ×100). (C) Lipid vesicles were abundant in some tumor cells (H&E staining, with original magnification
×400). (D) The tumor cells had enlarged eosinophilic cytoplasm and eccentrically-displaced
nuclei, exhibiting a rhabdoid phenotype (H&E staining, with original magnification
×200). (E) Pseudo-nuclear invaginations were another distinctive feature of tumor cells (H&E
staining, with original magnification ×400). (F) The sclerotic stroma dispersed tumor cells into isolated small nests (H&E staining,
with original magnification ×100). The vessels in between were usually dilated and
some of them resembled the changes of papillary endothelial hyperplasia (inserted
panel, H&E staining, with original magnification ×400).

The majority of the neoplastic cells were enlarged with marked eosinophilic cytoplasm
that sometimes contained sharply delineated lipid vacuoles. A few cells showed highly
vacuolated and clear cytoplasm. The nuclei were generally eccentric, mildly to moderately
pleomorphic with coarse granular chromatin, resembling the rhabdoid cells (Figure
1C, D). The nucleoli were inconspicuous. However, there were many prominent intranuclear
cytoplasmic pseudoinclusions (Figure 1E). Mitotic figures were detectable but were exceedingly rare.

The tumor cells displayed an alternation of cellular and reticular growth patterns.
In the former, zellballen-like cellular clusters of neoplastic cells enclosed discrete
and sparse vessels. In the latter, trabeculae of neoplastic cells were traversed by
abundant slit-like sinusoids. In regions with extensive stromal fibrosis, the tumor
cells were dispersed and progressively replaced by hyalinized collagen. The coupled
vessels were remained and were frequently dilated (Figure 1F).

Reticular fibers enclosed both tumor cells and vasculature in the areas of reticular
growth pattern, but barely surrounded the vessel walls in the regions of cellular
growth pattern (Figure 2). PAS staining for glycogen was negative in tumor cells.

Figure 2.Reticulins were found around individual tumor cells as well as the vascular channels
(reticulin growth pattern, right field). Alternatively, only the vascular channels were delineated (cellular growth pattern,
left field) (Reticular staining, with original magnification ×200).

Discussion

Renal haemangioblastoma (RHB) is extremely uncommon since only four cases were definitely
reported previously (Table 2). Our case was specifically in line with the diagnostic clues of RHB suggested by
Ip et al [5] and Verine et al [6]. Those characteristics included circumscribed borders, paucity of mitotic figures,
fine vacuoles in some tumor cells indicating presence of intracytoplasmic lipids,
and a rich capillary network. The immunoprofiles (S100 +, NSE+, a-inhibin + and AE1/AE3-)
also conformed to those of haemangioblastomas. However, the majority of the tumor
cells in our case showed rhabdoid features, which may be easily mistaken for other
rhabdoid tumors that are known to occur in the kidney.

Table 2. Clinicopathological characteristics of the reported sporadic hemangioblastomas in
the kidney

In our opinion, the first differential consideration is the malignant rhabdoid tumors
(MRTs). Although most of MRTs afflict young children, there still are sporadic cases
affecting adults [7,8]. Several features seen in our case do not support the diagnosis of MRTs: (i) MRTs
generally show vesicular chromatin, prominent nucleoli and hyaline intracytoplasmic
inclusion [8]. The neoplastic cells in our case demonstrated dark-stained and coarse granular chromatin,
and lack the discernable nucleoli as well as cytoplasmic inclusions. (ii) MRTs are
devoid of the cytoplasmic lipid droplets and arborizing stromal vasculature, characterized
by haemangioblastomas. (iii) Immunohistochemically, MRTs occasionally are focally
positive for S100 and NSE [9], but a-inhibin staining was not shown. The features are different from the extensive
expression of S100, NSE and a-inhibin seen in RHB. (IV) MRTs are a highly invasive
and lethal neoplasm with a proliferation index of Ki-67 around 95% [8]. In contrast, the extremely low Ki-67 index and rare mitosis indicate an indolent
behavior of our case.

Another necessary differential consideration is renal cell carcinomas with rhabdoid
features (RCCR), which have been previously described [10,11]. RCCR are predominantly composed of large polygonal cells with eccentric nuclei and
eosinophilic cytoplasm. Of the 23 cases analyzed by Gökden et al. [10], RCCR showed a diffuse NSE staining (79% of cases) and focal positive staining for
EMA (47% of cases) and S-100 (37% of cases), whereas cytokeratin expression was decreased
(56% of cases). Obviously, there are many morphologic and immunophenotypic features
that markedly overlap with our present case. Nevertheless, compared with RCCR, the
tumor cells of our case did not display the vesicular nuclei and prominent nucleoli.
Furthermore, RHB is characterized by abundant vascular networks, which are strikingly
reduced in RCCR [11]. In addition, RHB demonstrates negative PAS staining for glycogen, whereas this staining
is positive in RCCR [11]. The low Ki-67 index in our case is also not compatible with the high proliferative
index in RCCR [12].

Other neoplasms with rhabdoid features possibly that need to be considered before
making the diagnosis of RHB include epithelioid angiomyolipoma (HMB-45+ and Melan-A+), malignant melanoma with rhabdoid features (HMB-45+ and Melan-A+) [13], paraganglioma (synaptophysin+, chromogranin+ and a-inhibin-), epithelioid leiomyosarcoma with rhabdoid features (SMA+, desmin+ and S100-) [14], and epithelioid malignant peripheral nerve sheath tumor (a-inhibin-) [15].

Interestingly, focal CD10 positivity was observed in some tumor cells of our present
case. In the normal kidney, CD10 stains glomerular cells and proximal convoluted tubules,
and participates in the regulation of water and sodium metabolism [16]. Thus, CD10 expression in RHB seemingly substantiates the earlier hypothesis that
haemangioblastomas are derived from pluripotent mesenchymal cells, and partially acquire
some site-specific markers of their parental organs during pathogenesis [4]. Many studies have suggested CD10 is a powerful marker in the differentiation between
renal cell carcinoma and haemangioblastoma since it usually demonstrates positive
staining in renal cell carcinoma while is steadily negative in haemangioblastoma [17]. Our result indicates that caution should be taken on evaluating the differential
efficacy of this reagent. Noticeably, Verine et al. [6] reported a negative result of CD10 staining in their case of RHB. The reasons for
the discrepancy remain unknown, and probably either reflect the intrinsic disparities
of expressional profiles between the two specimens, or may be just caused by different
antibodies used.

Some investigators have suggested that RHB would not be as rare if it had got wider
recognition as a primary renal tumor [5,6]. So it is undoubtedly necessary to be aware of the clinicopathologic characteristics
of RHB. From the available data, RHB commonly occurs in the elderly people (range
55 to 71 years) and there is no sex predilection. The right kidney seems more prone
to be affected and the superior pole is likely the preferential site of mass development.
Grossly, these tumors displayed a solid cut surface, though cystic changes were occasionally
observed. Architecturally, the lesions were consistently composed of cellular and
paucicellular regions. In the cellular areas, the tumor could be subclassified as
reticular and cellular variants analogous to cerebellar haemangioblastoma [18]. In the paucicellular zones, stromal fibrosis was prominent. Cytologically, the neoplastic
cells in RHB generally contained mild to remarkably eosinophilic cytoplasm and frequently
outnumbered the clear cells with rich lipid droplets. The nuclei were often enlarged
and hyperchromatic, and frequently displayed some pleomorphism. In addition to the
positivity for S100, a-inhibin and NSE, focal expression of EMA, SMA, MSA and calponin
were also noted [5]. Nevertheless, Cytokeratins, HMB-45, Melan-A, chromogranin, calretinin, and Myoglobin
were characteristically negative.

Compared with cerebellar haemangioblastoma (CHB), RHB manifest with some different
features. For instance, RHB incidence peaks in the sixth decade compared to the fourth
decade of CHB [19]. RHB usually presents as a solid mass, whereas 65 percent of CHB manifest as a cystic
mass [20]. The acidophilic cytoplasm and pleomorphic nuclei that are frequently present in
renal tumors are usually not seen in CHB. Stromal hyalinization in RHB is also more
prominent than that in CHB. However, the immunophenotype and benign behaviors of RHB
reflect the essential consistency with CHB.

Conclusions

We have presented another case of RHB, which demonstrates distinctive rhabdoid features
and focal CD10 expression. The tumor cells of RHB generally show abundant acidophilic
cytoplasm and pleomorphic nuclei, whereas the characteristic stromal cells with finely-vacuolated
lipid droplets are not usually prominent. Diffuse expression of S100, a-inhibin and
NSE are very helpful to narrow down the differential diagnoses. The unexpected positive
staining of CD10 in RHB should be particularly concerned. RHB have excellent prognosis,
and tumor necrosis and nuclear pleomorphism do not seem to affect the prognosis. Most
importantly, RHB should be included in the differential diagnosis of primary renal
tumors.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

W-HY designed the study, performed the histological and immunohistochemical evaluation,
literature review and drafted the manuscript. JL participated in histological diagnosis
and immunohistochemical evaluation, literature review and revised the manuscript.
JKCC participated in histological diagnosis. All authors read and approved the final
manuscript.

Consent

Written informed consent was obtained from the patient for publication of this case
report and accompanying images. A copy of the written consent is available for review
by the Editor-in Chief of this Journal.

Acknowledgements

The authors express their sincere appreciation of the language editing assistance
given by Keiyan Sy, MD, Department of Laboratory Medicine and Pathobiology, University
of Toronto, Canada and Laibao Sun, MD, Department of Anatomic Pathology, Sunnybrook
Health Sciences Centre, Toronto, Canada.